A pharmacokinetic study was conducted with crossover design in 40 healthy subjects
who were each administered a single intravenous dose as a 2-hour infusion of either
generic racemic leucovorin (400 mg/m2) or FUSILEV (200 mg/m2).

Indications and Usage

Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.

Use in combination chemotherapy with 5-FU in the palliative treatment of patients with advanced metastatic colorectal cancer.

Limitations of Use

FUSILEV is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause
a hematologic remission while neurologic manifestations continue to progress.

Important Safety Information

Contraindications

FUSILEV is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

Warnings and Precautions

Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute.

FUSILEV enhances the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported
in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the
palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the
toxicities observed in patients treated with the combination of FUSILEV and 5-FU are qualitatively similar to those observed
with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of
greater severity and of prolonged duration in patients treated with the combination.

Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was
associated with increased rates of treatment failure in a placebo-controlled study.

Adverse Reactions

Allergic reactions were reported in patients receiving FUSILEV.

The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving FUSILEV in combination with 5-FU were diarrhea, nausea and stomatitis.

Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving FUSILEV as rescue after high dose
methotrexate therapy.

Drug Interactions

FUSILEV may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients.

FUSILEV adverse event profile

Adverse reactions (≥10% in either arm) in patients with advanced metastatic colorectal cancer